Ther are two to four million people with Alzheimer's disease (AD) in the U.S. alone and the cost of their care is currently estimated at 100 billion dollars. Current therapy is limited to symptomatic relief. The number of patients in which the disease is predicted by a single gene is relatively low (5-10%), however, one form of the cholesterol-binding protein apolipoprotein E (apoE) is strongly associated with the risk of AD in the majority (40-70%) of late-onset cases. ApoE has been shown to exhibit neurotoxic activity with isoform specificity that parallels the risk of disease. We propose to determine the feasibility of identifying novel therapeutic agents for treating AD using a sensitive in vitro cell death assay system in which apoE neurotoxicity is prevented. This initial screen will define the most suitable candidates from which therapeutic compounds will be developed. The results will lead to a Phase II proposal which will further evaluate the lead compounds in other efficacy and toxicity studies for eventual Phase I clinical testing. PROPOSED COMMERCIAL APPLICATION: Proposed commercial application not available.